BACKGROUND: Smoking has been associated with cervical cancer. We examined whether smoking increases the risk for high-grade cervical lesions in women with high-risk human papillomavirus (HPV) infection. METHODS: In a population-based cohort study, 8,656 women underwent a structured interview, and subsequently cervical cells were obtained for HPV DNA testing. Women with high-risk HPV infection and no prevalent cervical disease at baseline (n=1,353) were followed through the Pathology Data Bank for cervical lesions for up to 13 years. Separate analyses of women with persistent high-risk HPV infection were also conducted. Hazard ratios (HRs) for a diagnosis of cervical intraepithelial neoplasia grade 3 or worse/high-grade squamous intraepithelial lesions or worse (CIN3+) and the corresponding 95% confidence intervals (CIs) were calculated in the 2 groups. RESULTS: Among high-risk HPV positive women an increased risk for CIN3+ was associated with long-term smoking (=10 years) and heavy smoking (=20 cigarettes/day). In the subgroup of women with persistent HPV infection heavy smoking was also associated with statistically significantly higher risk for CIN3+ than never smoking (HR, 1.85; 95% CI, 1.05-3.22, adjusted for length of schooling, parity and HPV type at baseline). The average number of cervical cytology screening tests per year during follow-up did not explain the differences in risk in relation to smoking (p=0.4). CONCLUSIONS: Smoking is associated with an increased risk for subsequent high-grade cervical lesions in women with persistent high-risk HPV infection. Impact: Our study adds to the understanding of the role of smoking in the natural history of HPV and cervical carcinogenesis.